Mechanisms of Morbid Hearing Loss Associated with Tumors of the Endolymphatic Sac in Von Hippel-Lindau Disease

ORIGINAL CONTRIBUTION

Mechanisms of Morbid Hearing Loss Associated With Tumors of the Endolymphatic Sac in von Hippel-Lindau Disease

John A. Butman, MD, PhD Context Endolymphatic sac tumors (ELSTs) are associated with von Hippel-Lindau H. Jeffrey Kim, MD disease and cause irreversible sensorineural hearing loss (SNHL) and vestibulopathy. Martin Baggenstos, MD The underlying mechanisms of audiovestibular morbidity remain unclear and optimal timing of treatment is not known. Joshua M. Ammerman, MD Objective To define the mechanisms underlying audiovestibular pathophysiology James Dambrosia, PhD associated with ELSTs. Athos Patsalides, MD Design, Setting, and Patients Prospective and serial evaluation of patients with Nicholas J. Patronas, MD von Hippel-Lindau disease and ELSTs at the National Institutes of Health between May 1990 and December 2006. Edward H. Oldfield, MD Main Outcome Measures Clinical findings and audiologic data were correlated Russell R. Lonser, MD with serial magnetic resonance imaging and computed tomography imaging studies NDOLYMPHATIC SAC TUMORS to determine mechanisms underlying audiovestibular dysfunction. (ELSTs) are highly vascular, be- Results Thirty-five patients with von Hippel-Lindau disease and ELSTs in 38 ears (3 nign, but locally aggressive neo- bilateral ELSTs) were identified. Tumor invasion of the otic capsule was associated with plasms of the endolymphatic larger tumors (P=.01) and occurred in 7 ears (18%) causing SNHL (100%). No evi- systemE that often destroy the surround- dence of otic capsule invasion was present in the remaining 31 ears (82%). SNHL developed in 27 of these 31 ears (87%) either suddenly (14 ears; 52%) or gradually (13 ing temporal bone (FIGURE 1).1-3 ELSTs ears; 48%) and 4 ears had normal hearing. Intralabyrinthine hemorrhage was found occur sporadically but are a common in 11 of 14 ears with sudden SNHL (79%; PϽ.001) but occurred in none of the 17 manifestation of von Hippel-Lindau dis- ears with gradual SNHL or normal hearing. Tumor size was not related to SNHL (P=.23) ease (VHL), in which they can also oc- or vestibulopathy (P=.83). cur bilaterally.3,4 ELSTs are associated Conclusions ELST-associated SNHL and vestibulopathy may occur suddenly due to with significant audiovestibular mor- tumor-associated intralabyrinthine hemorrhage, or insidiously, consistent with endo- bidity, including sudden irreversible lymphatic hydrops. Both of these pathophysiologic mechanisms occur with small tu- hearing loss.3-5 Despite the effects of mors that are not associated with otic capsule invasion. ELSTs and their association with VHL, JAMA. 2007;298(1):41-48 www.jama.com the underlying pathophysiologic mechanisms of audiovestibular dys- cols in patients with VHL including se- Information from these evaluations now function associated with ELSTs, the rial high-resolution magnetic resonance provides insight into the mechanisms high incidence of unexplained audio- imaging (MRI) and computed tomo- of symptom formation, early imaging vestibular dysfunction in patients with graphic (CT) imaging with audiologic features, and the natural history of VHL, and the optimal timing of treat- evaluations have been developed and ELSTs. To determine the mechanisms ment for ELSTs have not been de- used at the National Institutes of Health. underlying hearing loss and other ves- fined. Since clinicians have determined the Author Affiliations: Diagnostic Radiology Depart- Biostatistics Branch (Dr Dambrosia), National Insti- presence of ELSTs in the VHL syn- ment, The Clinical Center of the National Institutes tute of Neurological Disorders and Stroke, National of Health (Drs Butman, Patsalides, and Patronas); Institutes of Health, Bethesda, Maryland. drome, prospective screening proto- Neuro-Otology Branch, National Institute on Deaf- Corresponding Author: John A. Butman, MD, PhD, ness and Other Communication Disorders, National Diagnostic Radiology Department, The Clinical Cen- See also Patient Page. Institutes of Health (Dr Kim); Surgical Neurology Branch ter of the National Institutes of Health, Bldg 10, Room (Drs Baggenstos, Ammerman, Oldfield, and Lonser), 1C365, Bethesda, MD 20892 ([email protected]).

Downloaded from www.jama.com on July 3, 2007 HEARING LOSS ASSOCIATED WITH TUMORS IN VON HIPPEL-LINDAU DISEASE tibulopathy in patients with ELSTs, we CT Imaging steady state acquisition, and 3- to 5-mm analyzed the serial imaging and clini- To determine the presence of otic cap- fluid-attenuated inversion recovery. Im- cal findings in consecutive patients with sule invasion and extent of bony ero- age resolution was less than 1 mm in VHL with ELSTs. sion by ELSTs, temporal bone CT plane in all cases. imaging (axial and coronal; 0.625- to Because the contents of the vestibu- 1.5-mm slice thickness; bone algorithm lar aqueduct may normally enhance on METHODS reconstruction kernel) was performed. high-resolution postcontrast T1- Patients For analysis purposes, ELSTs were di- weighted spoiled gradient recall se- Clinic charts, audiograms, MRI, and CT vided into 2 groups based on CT imaging quences, small in situ ELSTs were iden- images were analyzed for patients with evidence of otic capsule invasion by tu- tified by asymmetrical enhancement of VHL whose cases were monitored at the mor or lack thereof. the endolymphatic duct on MRI to- National Institutes of Health between gether with bony erosion of the ves- May 25, 1990, and December 18, 2006. Magnetic Resonance Imaging tibular aqueduct on CT imaging. The All patients were studied under Na- Inner ear MRI was used to identify the presence of intralabyrinthine hemor- tional Institute of Neurological Disor- extent of soft tissue mass in the tem- rhage was defined on MRI as abnor- ders and Stroke internal review board– poral bone and to evaluate signal within mal isolated intralabyrinthine increased approved protocols (NIH 79-N-0089 the sensory labyrinth. Because the stud- signal on precontrast T1-weighted im- and NIH 00-N-0140) after providing in- ies spanned several years, there was ages. Intralabyrinthine lipoma, which formed consent. Patients were prospec- some variation in technique commen- could also appear as a precontrast T1- tively monitored for the development surate with technical improvements in weighted hyperintensity, was ex- of audiovestibular symptoms and in- methodology. Before 1999, MRI included on fat-saturated MRI. To quan- cluded if diagnostic imaging showed cluded spin echo T1-weighted precon- tify and compare tumor size, the largest evidence of ELST. trast and postcontrast and fast spin echo tumor diameter was determined from T2-weighted sequences using slice a single axial slice using MRI and re- Imaging Studies thickness of 3 mm or less. After 1999, corded. Neuroradiologists blinded to the pres- examinations used 1.6-mm overlap- ence and degree of audiovestibular find- ping spoiled gradient recall T1- Clinical Evaluation ings reviewed all imaging studies and weighted precontrast and postcon- Patients underwent complete neurologic recorded the results. trast, T2-weighted fast induction of andaudiologicexaminations(see“Audio-

Figure 1. Anatomical Relationships of the Endolymphatic Sac

LRLeft Inner Ear, Superoposterior View Left Inner Ear, Axial Cross Section

Cochlea Utricle Saccule Carotid AREA OF Otic capsule Tympanic artery DETAIL External auditory cavity canal Cochlea CNVII Membranous Vestibule labyrinth Semicircular CNVIII canals CNVIII MASTOID PETROUS AIR CELLS CNVII TEMPORAL BONE Vestibule Otic capsule (DURA REMOVED) Vestibular aqueduct Posterior semicircular canal Endolymphatic duct Endolymphatic duct DUR A (in vestibular aqueduct) LEVEL OF AXIAL CROSS SECTION Endolymphatic Sigmoid sac Endolymphatic sinus Sigmoid sinus sac

The endolymphatic sac is located on the posteromedial surface of the petrous temporal bone, covered by dura. The endolymphatic duct lies within the vestibular aqueduct and connects the endolymphatic sac to the remainder of the membranous labyrinth. The bony otic capsule encases the membranous labyrinth. Tumors of the endolymphatic sac can result in hearing loss directly through invasion of adjacent sensory structures housed within the otic capsule or indirectly through intralabyrinthine hemorrhage or endolymphatic hydrops. CN indicates cranial nerve.

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Figure 2. Distribution of Ears With Endolymphatic Sac Tumors

38 Total ears with audiovestibular symptoms

7 Ears with otic capsule 31 Ears without otic capsule invasion invasion

7 Ears with sensorineural 27 Ears with sensorineural 4 Ears without sensorineural hearing loss hearing loss hearing loss

14 Ears with sudden onset of 13 Ears with gradual onset of sensorineural hearing loss sensorineural hearing loss

11 Ears with intralabyrinthine 3 Ears without intralabyrinthine 13 Ears without intralabyrinthine 4 Ears without intralabyrinthine hemorrhage hemorrhage hemorrhage hemorrhage

Distribution of 38 ears based on history, imaging, and clinical findings affected by endolymphatic sac tumors in 35 consecutive patients with von Hippel-Lindau disease. logic Assessment” section) at intervals of male [54%]; 16 male [46%]; FIGURE 2). Table. Findings in 38 Ears Affected by 6 to 24 months or when audiovestibular Bilateral ELSTs were detected in 3 pa- Endolymphatic Sac Tumors in 35 Patients symptoms developed. The presence of tients (9%). Mean age (SD) at symp- With von Hippel-Lindau Disease audiovestibular symptoms including tin- tom onset was 31 (13) years (range, Finding No. (%)a nitus, vertigo, aural fullness, and specific 11-63 years). Mean (SD) follow-up time Sex, No. (%) of patients evidenceofothercranialnerveabnormali- was 7.78 (4.75) years (range, 0.25-16 Female 19 (54) Male 16 (46) ties were recorded at each visit. years). All patients with imaging evi- Tumor location dence of ELST developed audiovestibu- Left 23 (61) Audiologic Assessment Right 15 (39) lar symptoms including hearing loss, Bilateral 3 (9) Audiometric evaluations were per- tinnitus, vertigo, aural fullness, aural Otic capsule invasion formed in conjunction with clinical Yes 7 (18) pain, facial nerve weakness, or aural No 31 (82) evaluations and included air and bone pain and facial nerve weakness com- Signs and symptoms conduction, pure tone thresholds, and bined (TABLE). Nineteen patients (54%) Sensorineural hearing loss 34 (89) None 4 (11) speech discrimination assessment. Hear- had a triad of the most common symp- Mild 6 (16) ing loss was characterized as mild (26-40 toms that included SNHL, tinnitus, and Moderate 10 (26) Profound 18 (47) dB), moderate (41-55 dB), moderate to vertigo (9 additional patients [26%] had Tinnitus 27 (71) severe (56-70 dB), severe (71-90 dB), or 2 of these symptoms). Mean tumor di- Intermittent 14 (37) Ն Continuous 13 (34) profound ( 91 dB). The time span over ameter (SD) was 1.4 cm (1.0 cm) Vertigo 24 (69) which the sensorineural hearing loss (range, 0.2-5.2 cm). Tumor size was not Intermittent 23 (85) (SNHL) evolved was classified as sud- associated with SNHL (P=.23) or with Continuous 4 (15) Ͻ Aural fullness 14 (37) den ( 24 hours) or gradual (weeks- audiovestibular symptoms (analysis of Intermittent 12 (32) months). StatXact 6, version 6.2.0 (Cy- variance; P=.83; FIGURE 3). Seven ears Continuous 2 (5) Aural pain (continuous) 4 (11) tel Inc, Cambridge, Massachusetts) and (6 patients; 18%; P=.01) had tumor- Facial nerve weakness (continuous) 2 (5) SPSS for Windows, version 11.5.0 (SPSS associated otic capsule invasion and 31 a Data are for number of ears unless otherwise noted. Inc, Chicago, Illinois). P level of signifi- ears (30 patients; 82%) had no evi- cance was less than .05. dence of otic capsule invasion lateral ELSTs. One patient had unilat- (Figure 2). eral invasion of the otic capsule and the RESULTS other had bilateral invasion of the otic Overall Patient Ears With Otic Capsule Invasion capsule. Mean (SD) age at audioves- and Tumor Characteristics Clinical Findings. Seven ears (4 right; tibular symptom onset was 32 (13) A total of 38 ears affected by ELSTs (23 3 left) among 6 patients (2 male; 4 fe- years (range, 14-34 years). Overall, left [61%]; 15 right [39%]) were iden- male) had ELSTs that invaded the otic mean (SD) follow-up was 7.68 (4.43) tified in 35 patients with VHL (19 fe- capsule. Two of these patients had bi- years (range, 3.25-14.83 years).

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tent in 17 (81%). Aural fullness was Figure 3. Analysis of Correlation Between Tumor Size and Hearing Loss in Patients With von Hippel-Lindau Disease continuous in 2 affected ears (20%) and intermittent in 8 (80%). Aural pain was Otic capsule invasion No otic capsule invasion continuous in 3 affected ears (100%). (n = 7 ears) (n = 31 ears) 60 60 Imaging. Thirty (97%) of 31 ELSTs without otic capsule invasion had 50 50 imaging features consistent with an 40 40 ELST. The mean (SD) tumor diameter for these tumors was 1.2 cm (0.7 cm) 30 30 (range, 0.2-2.6 cm), which was smaller

20 20 (analysis of variance; P=.01) than those

Tumor Diameter, mm Diameter, Tumor mm Diameter, Tumor ELSTs that invaded the otic capsule 10 10 (mean (SD) diameter 2.2 cm [1.6 cm]; range, 0.5-5.2 cm). One ELST (3%) was 0 0 Mild to Moderate Severe to Profound None Mild to Moderate Severe to Profound not visible on MRI or CT imaging, but Hearing Loss Hearing Loss was suspected because of intralabyrin- Thirty-eight ears affected by endolymphatic sac tumors in 35 patients with von Hippel-Lindau disease were thine hemorrhage (visible on T1- analyzed for correlation between tumor size and presence of sensorineural hearing loss. There was no corre- weighted MRI) that corresponded with lation (analysis of variance; PϾ.05) between tumor size and sensorineural hearing loss in ears with or without otic capsule invasion. sudden SNHL, vertigo, and tinnitus. Surgical exploration revealed a small ELST (2 mm) that was resected. Hyperintense signal on precontrast When otic capsule invasion was de- (Figure 4). Mean (SD) tumor diameter T1- and fluid attenuated inversion re- tected, SNHL was present. The SNHL was 2.2 cm (1.6 cm) (range, 0.5-5.2 cm). covery-weighted MRI, indicative of in- was mild in 1 ear and severe to pro- tralabyrinthine hemorrhage (FIGURE 5), found in the remaining 6 ears Ears Without Otic Capsule Invasion was seen in 11 of the 14 ears (79%) in (Figure 3). Additional audiovestibu- Clinical Findings. Thirty-one ears (11 which sudden SNHL was identified lar and cranial nerve findings in- right, 20 left) among 30 patients (14 clinically (␹2 test; PϽ.001). In the 13 cluded vertigo (4 patients; 67%), tin- male, 16 female) were affected by ELSTs ears without otic capsule invasion in nitus (4 ears; 57%), aural fullness (4 that did not invade the otic capsule. One which SNHL occurred gradually,there ears; 57%), facial nerve weakness (1 pa- patient had bilateral ELSTs that were not was no evidence of intralabyrinthine tient; 17%), and aural pain (1 ear; 14%). associated with otic capsule invasion. hemorrhage (on precontrast T1- Vertigo was intermittent in all patients Mean (SD) age at audiovestibular symp- weighted or fluid attenuated inver- with vertigo (4; 100%). Tinnitus was tom onset was 32 (13.1) years (range, sion recovery MRI; FIGURE 6). Simi- continuous in 1 ear (25%) and inter- 11-63 years). Overall, mean (SD) fol- larly,none of the 4 patients without otic mittent in 3 ears (75%). Aural fullness low-up was 95.4 (56.2) months (range, capsule invasion and normal hearing was intermittent in all affected ears (4; 3-192 months). had evidence of intralabyrinthine hem- 100%). Aural pain was continuous in Twenty-seven of the 31 ears (87%) orrhage. There was no correlation be- the 1 affected patient (100%). without otic capsule invasion had SNHL tween tumor size and the presence of Imaging. All ELSTs with otic capsule (4 ears had normal hearing). SNHL in intralabyrinthine hemorrhage (univari- invasion had the typical imaging fea- these ears was mild to moderate in 15 ate analysis of variance; P=.13) among tures of ELST (FIGURE 4). Nonen- ears (56%) and severe to profound in the ELSTs without otic capsule inva- hanced T1-weighted MRI revealed 12 ears (44%). The hearing loss in the sion. ELSTs as heterogeneous in intensity 27 patients with SNHL occurred either with associated areas of hyperinten- suddenly (14 ears; 52%) or gradually COMMENT sity,suggestive of intratumoral hemor- (13 ears; 48%) over months to years. ELSTs in VHL Disease rhage and cholesterol granuloma for- Additional audiovestibular findings in- VHL has an incidence of 1 in 39 000 in- mation (Figure 4). Precontrast cluded tinnitus (23 ears; 74%), ver- dividuals.6 It is an autosomal dominant isointense portions of the ELSTs tigo (21 patients; 70%), aural fullness neoplasia syndrome that is the result of enhanced on postcontrast T1-weighted (10 ears; 32%), aural pain (3 ears; 10%), a germline mutation or deletion of the MRI. ELSTs on CT imaging were and facial nerve weakness (1 ear; 3%). VHL tumor suppressor gene on the short isodense with gray matter, with foci of Tinnitus was continuous in 12 af- arm of chromosome 3.7-9 VHL is associ- bone density indicating bone destruc- fected ears (52%) and intermittent in ated with variable penetrance and hetero- tion and permeation, centered on the 11 (48%). Vertigo was continuous in 4 geneous clinical findings. Affected indi- region of the vestibular aqueduct affected patients (19%) and intermit- viduals often develop benign and

Downloaded from www.jama.com on July 3, 2007 HEARING LOSS ASSOCIATED WITH TUMORS IN VON HIPPEL-LINDAU DISEASE malignant visceral and central nervous with tumors that were significantly larger and vestibulopathy in patients without system lesions.8,10 Visceral manifesta- than those that did not invade the otic otic capsule invasion, supports the hy- tions include renal cysts and carcino- capsule. Analysis of tumor size and its pothesis that mechanisms other than otic mas, pheochromocytomas, pancreatic relationship to the presence of SNHL and capsule destruction by tumor expan- cysts and neuroendocrine tumors, as well audiovestibular symptomatology re- sion underlie the audiovestibular mor- as reproductive adnexal organ cystad- vealed no association (Figure 3). The lack bidity linked to ELSTs. enomas.8,11,12 Central nervous system of correlation between tumor size and While we did not find a link be- manifestations include retinal, cerebel- SNHL, as well as the presence of SNHL tween tumor size and SNHL, Manski et lar, spinal cord, and brainstem hemangioblastomas, as well as ELSTs.8,10 Figure 4. Large Endolymphatic Sac Tumor With Invasion of the Otic Capsule Associated ELSTs were clinically established as With Profound Hearing Loss part of the VHL syndrome by Manski et al3 and confirmed by genetic analy- A Precontrast Computed Tomography Image ses of Vortmeyer et al.13,14 While these tumors rarely occur in the general Cochlea population, they are found frequently CNVII/VIII in patients with VHL by MRI or CT Vestibule imaging with an estimated incidence of 11% to 16%.3,4,8,15 VHL is the only con- MASTOID dition identified that is associated with AIR CELLS 3,4 Bone erosion bilateral ELSTs. While 9% of pa- by ELST tients in this study had bilateral ELSTs, CEREBELLUM Posterior previous reports have suggested that bi- semicircular canal lateral tumors may occur in as many as

15% to 30% of patients with VHL with B Precontrast T1-Weighted Magnetic Resonance Image ELSTs.3,16 These previous estimates may be higher in part because they were Cochlea based on summaries of case reports or CNVII/VIII Vestibule isolated smaller series. All patients in this series developed audiovestibular symptoms. Analogous with a pathophysiologic process within the en- Sigmoid ELST sinus dolymphatic system, most patients presented with a triad of findings frequently associated with Menière disease that includes hearing loss, tinnitus, and Peripheral hemorrhage vertigo (Table).1,4,17 This often led to a referral diagnosis of Menière disease be- C Postcontrast T1-Weighted Magnetic Resonance Image fore discovery of an ELST. Consistent with previous reports that describe a 90% Cochlea incidence of either gradual or sudden SNHL in patients with ELST,3,4,18 the Vestibule most common ELST-associated clinical finding in this series was hearing loss. Sigmoid SNHL occurred in 31 patients (89%) or sinus 34 of the affected ears (89%) and was fre- ELST quently moderate or profound (Figure 2). Other less frequent ELST- associated findings included aural fullness, aural pain, facial nerve weakness, Invasion of the otic capsule by a large endolymphatic sac tumor (ELST) in a 38-year-old patient with von Hippel- and aural pain and facial nerve weak- Lindau disease and profound hearing loss. A, Axial precontrast computed tomography (CT) image demon- ness combined (Table). strates extensive temporal bone destruction (black arrowhead) with erosion into the otic capsule at the posterior semicircular canal (black arrow). B, Axial precontrast T1-weighted magnetic resonance image (MRI) Consistent with the anatomic origin demonstrates isointense tumor associated with hyperintense peripheral hemorrhage (white arrowheads). C, and known progressive erosive nature of Axial postcontrast T1-weighted MRI demonstrates enhancement of the bulk of the ELST, which directly ex- tends into the labyrinth (white arrow). CN indicates cranial nerve. ELSTs, otic capsule invasion occurred

Downloaded from www.jama.com on July 3, 2007 HEARING LOSS ASSOCIATED WITH TUMORS IN VON HIPPEL-LINDAU DISEASE al3 reported that increased tumor size made the definitive clinical association tumors that were associated with long- was associated with loss of functional of ELSTs in VHL, patients with VHL standing hearing loss at diagnosis. Im- hearing in 13 patients with VHL with 15 were not routinely screened for ELSTs. provements in imaging resolution, as ELSTs. The most likely reason for this Thus, detection of ELSTs, including well as the development of targeted clini- difference is related to the timing of those in the series of Manski et al,3 were cal and imaging screening protocols, ELST discovery. Until Manski et al3 delayed and patients frequently had large now permit early detection of very small ELSTs and their effects on the inner ear. The results of these studies, as de- Figure 5. Small Endolymphatic Sac Tumor With Intralabyrinthine Hemorrhage Associated scribed in this series of patients, reveal With Sudden Hearing Loss that audiovestibular morbidity occurs frequently with small ELSTs (2-3 mm Precontrast Computed Tomography Image A in diameter; Figure 3). Cochlea The detection of smaller ELSTs and CNVII/VIII their associated effects (ie, intralabyrinthine hemorrhage) give insight into the mechanism of the previously reported high incidence of audiovestibular dysfunction (including unexplained sudden hearing loss) in patients Vestibule with VHL without radiographic evidence of ELST.3,4 Using serial high- ELST resolution MRI and CT imaging with specific sequences to evaluate the in- B Precontrast T1-Weighted Magnetic Resonance Image ner ear, we detected several small tumors (Ͻ5 mm diameter) and found Cochlea that a large number of patients in this CNVII/VIII study (29%) had intralabyrinthine hem- Intralabyrinthine orrhage that corresponded with sud- hemorrhage den SNHL that may not have been detected using lower-resolution imaging Vestibule or imaging that was not clinically correlated with audiovestibular dysfunction (ie, before the inclusion of ELSTs

ELST in the VHL syndrome). This point is underscored by the detection of a small

C Fluid Attenuated Inversion Recovery (FLAIR) Magnetic Resonance Image ELST by the presence of intralabyrinthine hemorrhage on MRI and confirmed surgically to be in the vestibu- Cochlea Intralabyrinthine lar aqueduct. hemorrhage CNVII/VIII Mechanisms of Hearing Loss Based on the relationship between the Vestibule imaging and clinical findings in these patients, 3 distinct mechanisms (either alone or in combination) may account for the audiovestibular morbidity as- ELST sociated with ELSTs. These include di- rect invasion of the otic capsule by tu- A small endolymphatic sac tumor (ELST) that did not involve the otic capsule in a 68-year-old patient mor, intralabyrinthine hemorrhage, and with von Hippel-Lindau disease and sudden hearing loss (normal to profound hearing loss on audiogram) resulting from intralabyrinthine hemorrhage. A, Axial computed tomography (CT) image demonstrates ero- endolymphatic hydrops. sion of the posterior temporal bone by an ELST (black arrowhead) located at the vestibular aqueduct with no extension anteriorly toward the otic capsule. Axial magnetic resonance images (MRIs) of the tem- Otic Capsule Invasion by Tumor poral bone, B (T1-weighted) and C (FLAIR), reveal a hyperintense signal (black arrowheads) in the location of the tumor. Evidence of intralabyrinthine hemorrhage is seen in the vestibule and in the cochlea (white Because otic capsule destruction is a arrowheads). The morphology of the labyrinth of the inner ear is normal in all images. CN indicates well-described mechanism of hearing cranial nerve. loss and vestibulopathy and because

Downloaded from www.jama.com on July 3, 2007 HEARING LOSS ASSOCIATED WITH TUMORS IN VON HIPPEL-LINDAU DISEASE previous descriptions of ELST- tinnitus, and vertigo) typical of Me- hearing loss was found to have endo- associated hearing loss and vestibu- nière disease, suggesting that endolym- lymphatic hydrops and a microscopic lopathy occurred most often in the con- phatic hydrops develops in patients with ELST on postmortem histopathology.2 text of large tumors, previous reports ELSTs (Figure 2; Table).4 In support of Blockage of endolymphatic sac resorb- emphasized that hearing loss associ- this, a patient with VHL and antemor- tion of endolymph, inflammation in re- ated with ELSTs was the result of di- tem symptoms consistent with Menière sponse to hemorrhage, or excessive pro- rect invasion of the otic capsule by tu- disease, including tinnitus, vertigo, and duction of fluid by the tumor may mor.1,4,19,20 Similarly, this report demonstrates that larger tumor size is associated with radiographic evidence Figure 6. Small Endolymphatic Sac Tumor Associated With Gradual Hearing Loss of otic capsule invasion. Although it is Precontrast Computed Tomography Image possible that diagnostic imaging could A miss detection of histologic invasion of Cochlea the otic capsule, previous reports of small ELSTs with imaging evidence of CNVII/VIII an intact otic capsule did not have histologic evidence of otic capsule invasion.2,5,16 When an ELST directly erodes Vestibule into the inner ear, it destroys the mem- MASTOID branous labyrinth and disrupts endo- CEREBELLUM AIR CELLS lymphatic flow, causing hearing loss Bone erosion by ELST and vestibulopathy (Figure 4). Vestibular aqueduct

Intralabyrinthine Hemorrhage B Precontrast T1-Weighted Magnetic Resonance Image The results described in this study indicate that acute intralabyrinthine hemor- Cochlea rhage by an ELST explains the frequent occurrence of irreversible, sudden, and significant hearing loss that occurs in pa- CNVII/VIII Vestibule tients with ELSTs (Figure 5).2-4 This is supported by the presence of intralaby- ELST rinthine hemorrhage on MRI that was as- Sigmoid sinus sociated with sudden hearing loss in 77% Hemangioblastoma of ears with SNHL and no evidence of (Incidental) otic capsule invasion (Figure 2). These findings are further underscored by a pre- C Fluid Attenuated Inversion Recovery (FLAIR) Magnetic Resonance Image viously reported autopsy case demon- strating hemosiderin in the inner ear of a patient with VHL and sudden hearing Cochlea loss associated with a microscopic ELST,2 a patient with ELST with sudden hear- CNVII/VIII Vestibule ing loss coinciding with MRI evidence of intralabyrinthine hemorrhage,21 and ELSTs from patients with sudden SNHL ELST (without otic capsule invasion) who demonstrate intratumoral hemosiderin Hemangioblastoma and hemorrhage.5 The irreversibility of (Incidental) symptoms (particularly hearing loss) in such patients may be the result of neu- A small endolymphatic sac tumor (ELST) with no evidence of intralabyrinthine hemorrhage or otic capsule invasion in a 31-year-old patient with von Hippel-Lindau disease. The patient experienced gradual hearing ronal degeneration caused by hemor- loss (from normal hearing to moderate/severe loss on audiogram) over a 5-year period, intermittent ver- rhage, secondary inflammation, or both.2 tigo, and tinnitus. A, Axial precontrast computed tomography (CT) image demonstrates erosion of the posterior temporal bone by an ELST (black arrowhead) located at the vestibular aqueduct. Axial magnetic resonance images of the temporal bone, B (T1-weighted) and C (FLAIR), reveal a hyperintense signal (black Endolymphatic Hydrops arrowheads) in the location of the tumor. No evidence of intralabyrinthine hemorrhage is present as dem- The remaining patients presented with onstrated by the normal hypointense signal seen in the vestibule and cochlea in both B and C. CN indicates cranial nerve. a clinical syndrome (gradual hearing loss,

Downloaded from www.jama.com on July 3, 2007 HEARING LOSS ASSOCIATED WITH TUMORS IN VON HIPPEL-LINDAU DISEASE individually or in combination cause hy- hemorrhage are warranted in patients 10. Richard S, Campello C, Taillandier L, Parker F, Re- 4,22,23 sche F. Haemangioblastoma of the central nervous sys- drops. Production of peritumoral with VHL. tem in von Hippel-Lindau disease: French VHL Study fluid by ELSTs is analogous to the for- Author Contributions: Dr Butman had full access to all Group. J Intern Med. 1998;243(6):547-553. mation of peritumoral edema and cysts of the data in the study and takes responsibility for the 11. Linehan WM, Lerman MI, Zbar B. Identification of integrity of the data and the accuracy of the data analysis. the von Hippel-Lindau (VHL) gene: its role in renal cancer. that are frequently associated with cen- Study concept and design: Butman, Kim, Oldfield, JAMA. 1995;273(7):564-570. tral nervous system hemangioblasto- Lonser. 12. Libutti SK, Choyke PL, Alexander HR, et al. Clini- 24,25 8,23,26 Acquisition of data: Butman, Kim, Baggenstos, cal and genetic analysis of patients with pancreatic neu- mas and visceral tumors in VHL. Ammerman, Patsalides, Patronas. roendocrine tumors associated with von Hippel- Analysis and interpretation of data: Butman, Kim, Lindau disease. Surgery. 2000;128(6):1022-1027. Implications for Surveillance Dambrosia, Patronas, Oldfield, Lonser. 13. Vortmeyer AO, Choo D, Pack SD, Oldfield E, von Drafting of the manuscript: Butman, Lonser. Zhuang Z. Hippel-Lindau disease gene alterations as- and Treatment Critical revision of the manuscript for important in- sociated with endolymphatic sac tumor. J Natl Cancer Previously, the management of ELSTs tellectual content: Butman, Kim, Oldfield, Lonser. Inst. 1997;89(13):970-972. Statistical analysis: Dambrosia. 14. Vortmeyer AO, Choo D, Pack S, Oldfield E, Zhuang (particularly tumors that were small and Administrative, technical, or material support: Butman, Z. VHL gene inactivation in an endolymphatic sac tu- asymptomatic) has been conservative Kim, Oldfield, Lonser. mor associated with von Hippel-Lindau disease. Study supervision: Butman, Kim, Oldfield, Lonser. Neurology. 2000;55(3):460. because they have an uncertain natu- Financial Disclosures: None reported. 15. Megerian CA, McKenna MJ, Nuss RC, et al. Endo- ral history and are not considered ma- Funding/Support: This research was supported by the lymphatic sac tumors. Laryngoscope. 1995;105(8, 3,4 Intramural Research Program of the Clinical Center, pt 1):801-808. lignant or fast growing. This study National Institute of Neurological Disorders and Stroke 16. Megerian CA, Haynes DS, Poe DS, Choo DI, Ke- demonstrates that audiovestibular mor- and the National Institute on Deafness and Commu- riakas TJ, Glasscock ME III. Hearing preservation sur- bidity is frequently associated with nication Disorders at the National Institutes of Health. gery for small endolymphatic sac tumors in patients with Role of the Sponsor: The Intramural Research Pro- von Hippel-Lindau syndrome. Otol Neurotol. 2002;23 small tumors (those not invading the gram of the Clinical Center, National Institute of Neu- (3):378-387. otic capsule) and occurs by mecha- rologic Disorders and Stroke and the National Institute 17. Schuknecht HF, Belal AA. The utriculo- on Deafness and Communication Disorders at the Na- endolymphatic valve: its functional significance. J Laryn- nisms that include intralabyrinthine tional Institutes of Health did not participate in the de- gol Otol. 1975;89(10):985-996. hemorrhage and hydrops. Since sig- sign and conduct of the study; in the collection, man- 18. Thomassin JM, Roche PH, Braccini F, Epron JP, Pel- agement, analysis, and interpretation of the data; or in let W. Endolymphatic sac tumors [published in French]. nificant audiovestibular dysfunction, in- the preparation, review, or approval of the manuscript. Ann Otolaryngol Chir Cervicofac. 2000;117(5):274-280. cluding deafness, can occur suddenly 19. Hansen MR, Luxford WM. Surgical outcomes in pain a manner that is not related to tu- REFERENCES tients with endolymphatic sac tumors. Laryngoscope. 2004;114(8):1470-1474. mor size, early surgical intervention 1. Heffner DK. Low-grade adenocarcinoma of prob- 20. Rodrigues S, Fagan P, Turner J. Endolymphatic sac may be warranted. While this study able endolymphatic sac origin: a clinicopathologic study tumors. Otol Neurotol. 2004;25(4):599-603. of 20 cases. Cancer. 1989;64(11):2292-2302. 21. Gaeta M, Blandino A, Minutoli F, Pandolfo I. Sud- does not address the effectiveness of 2. Lonser RR, Kim HJ, Butman JA, Vortmeyer AO, Choo den unilateral deafness with endolymphatic sac adeno- surgical resection, several small opera- D, Oldfield E. 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